The research proposal within this application will use a molecular genetic approach to examine the hypothesis that a subpopulation of abnormal voltage-gated sodium channels expressed in skeletal muscle is responsible for the pathogenesis of the hereditary periodic paralyses. The hereditary periodic paralyses are a heterogenous group of nondystrophic autosomal dominant muscle diseases in which episodic failure of muscle membranes to generate and propagate action potentials leads to intermittent attacks of weakness or flaccid paralysis. Experimental evidence suggests that a noninactivating sodium conductance in surface membranes, possibly arising from a subpopulation of mutant sodium channels, leads to membrane depolarization and inactivation of normal voltage-gated sodium channels. The specific aims of this proposal are to clone and sequence the predominant human muscle voltage-gated sodium channels and identify restriction fragment length polymorphisms (RFLP) for use in chromosome mapping and linkage analysis in families with periodic paralysis. This information will lead to an improved understanding of the pathogenesis of this intriguing group of genetic muscle disorders, and help characterize the structure of a protein essential to the contraction of human striated muscle.